Therapeutic composition containing a phenol compound and propolis, which is useful against lipid capsid viruses, especially herpes viruses

ABSTRACT

PCT No. PCT/FR91/00186 Sec. 371 Date Oct. 11, 1992 Sec. 102(e) Date Oct. 11, 1992 PCT Filed Mar. 8, 1991 PCT Pub. No. WO91/13626 PCT Pub. Date Sep. 19, 1991The present invention concerns a novel therapeutic compositions comprising a phenol component and propolis which is useful in combating lipidic capside viruses, which contains (1) 100 to 650 parts by weight of phenol component for (ii) one part by weight of propolis. This novel composition is especially useful in the treatment of herpes, especially the diseases caused by the virus strains HSV1, HSV2 HSV1R.

FIELD OF THE INVENTION

The present invention relates to a novel therapeutic compositioncontaining a phenol component and propolis. This composition is userfulas an antiviral agent, in general against lipid capsid viruses(abbreviated to LCV's) and in particular against herpes viruses andtheir analogs which form part of the LCV group.

PRIOR ART

It is known that phenols have already been recommended in therapeuticsas anti-infective agents on account of their bacteriostatic ormycostatic properties.

Among these phenols, it is known, in particular from French patentFR-B-2 507 891, the article by W. SNIPES et al., Sciences, 187, pages64-65 (1975), and the articles by W. SNIPES et al. entitled "HydrophobicAlcohols and Di-tert-butyl Phenols as Antiviral Agents" and published inthe work "Symposium on the Pharmacological Effects of Lipids", pages63-73, The American Oil Chemists' Society, Champaign, Illinois (1978),that the BHT's of formula I below, namely the4-alkyl-2,6-di-t-butylphenols in which the alkyl group in the 4-positioncontains a linear hydrocarbon chain of 1 to 12 carbon atoms, haveinhibitory and/or virucidal effects on LCV's and especially herpesviruses. According to the second article by W. SNIPES et al. citedabove, it is known that the antiherpetic activity depends on the natureof the 4-alkyl group of the BHT and that the BHT which has an n-butylradical in the 4-position is virtually the only one active against HSV₂.

It is further known that propolis is a gummy substance recovered frombeehives. More precisely, it is a substance which the bees collect fromcertain plants, especially the scales of poplar and alder buds, amassand use for filling in cracks in the beehives, fixing the honeycombs andglazing the walls. In the field of apiculture, propolis is known to bethe antibiotic or disinfectant in the beehive, preventing bacteria andmolds from proliferating.

Crude propolis generally contains resins and balsamic substances(approximately 55-50% by weight), beeswax (approximately 30-35% byweight), ethereal oils (approximately 10% by weight) and pollens(approximately 5% by weight); see especially EP-A-0 061 508 (page 2,lines 1-28), EP-A-0 109 993 (page 1, lines 24-26) and E. M. SCHNEIDEWINDet al., Die Pharmazie 34, 103 (1978).

The antiviral properties of propolis extracted from beehives andpurified, against herpes viruses (especially HSV₁ and HSV₂) andinfluenza viruses (especially IV_(A)), are known especially from EP-A-0061 508 (page 3, lines 6-7) and EP-A-0 109 993 (page 2, lines 3-8; page10, lines 7-11; and page 11, lines 1-4) cited above, on the other hand,and EP-A-0 310 757 (page 3, lines 31-32), on the other.

Furthermore, a technique for the treatment of viral infections is knownfrom abstract n° 83-762896 in DATABASE WPI/L of Derwent PublicationsLtd, which relates to document R0-A-81 340, according to which technique(a) an alcoholic solution of propolis is administered orally and,simultaneously, (b) the locally affected areas are coated with analcoholic propolis composition which may contain a phenol component (inthe case in question, salicyclic acid as an anti-inflammatory agent)and/or vitamins; also, an antiherpes composition comprising propolis(one part by weight), phenol (0.5 part by weight) and menthol (one partby weight) is known from Chemical Abstracts CA 103, 220838q, whichrelates to document R0-A-86 003.

Now, it so happens that these last two documents neither describe norsuggest the synergistic composition of the invention, in which theweight ratio phenol component/propolis is between 100/1 and 650/1.

AIM OF THE INVENTION

According to the invention, a novel technical solution is recommendedwhich uses an antiviral composition comprising a synergistic mixture ofa phenol component and propolis in association.

This novel technical solution is advantageous in the sense that it makesit possible especially to reduce the practical doses previouslyrecommended in the antiviral indications for the phenol component andpropolis.

According to another feature of the invention, a method of preparingsaid composition is proposed.

SUBJECT OF THE INVENTION

It has now been found, surprisingly, that particular mixtures containinga phenol component and propolis have synergistic properties.

The therapeutic composition recommended according to the invention,which comprises a phenol component and propolis and which is useful asan antiviral agent against LCV's, contains

(i) from 100 to 650 parts by weight of phenol component to

(ii) one part by weight of propolis.

The method of preparation according to the invention consists in mixingthe phenol component with the propolis in a weight ratio phenolcomponent/propolis of 100/1 to 650/1.

ABBREVIATIONS

For convenience, the following abbreviations have been used in thepresent description:

BHT=2,6-di-t-butylphenol compound of formula I below [the letters BHToriginate historically from the expression "butylated hydroxy-toluene"]

BpA=bisphenol A

BpB=bisphenol B

Bzp=2-benzylphenol compound of formula II below

Cp=phenol component

EBV=Epstein Barr virus

Et=ethyl

EtO=ethoxy

HG1=2,6-di-t-butylparacresol (i.e. BHT of formula I in which R ismethyl)

HG4=2,6-di-t-butyl-4-butylphenol (i.e. BHT of formula I in which R isn-butyl) HGt4=2,4,6-tri-t-butylphenol (i.e. BHT of formula I in which Ris t-butyl)

HGt5=2,6-di-t-butyl-4-(2,2-dimethylpropyl)phenol [i.e. BHT of formula Iin which R is CH₂ C(CH₃)₃ ]

HG6=2,6-di-t-butyl-4-hexylphenol (i.e. BHT of formula I in which R isn-hexyl)

HGt8=2,6-di-t-butyl-4-(1,1,3,3-tetramethylbutyl)phenol [i.e. BHT offormula I in which R is C(CH₃)₂ --CH₂ --C(CH₃)₃ ]

HSV₁ =herpes simplex virus type 1

HSV₂ =herpes simplex virus type 2

HSV₁ R=herpes simplex virus type 1 resistant to acyclover [a referenceantiviral substance of the structural formula2-amino-1,8-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one]

IV_(A) =influenza virus type A

LCV=lipid capsid virus

Me=methyl

MeO=methoxy

Prp=propolis

R_(w) =weight ratio

RT=room temperature (15-20° C.)

TV=infectious titer of the virus sample

ZV=Zoster virus

DETAILED DESCRIPTION OF THE INVENTION

As indicated above, it is important from the synergy point of view forthe therapeutic composition according to the invention to comprise thephenol component (Cp) and the propolis (Prp) in a weight ratio R_(w)=Cp/Prp) of between 100/1 and 650/1 and advantageously with an R_(w) ofbetween 135/1 and 560/1.

The phenol component (Cp) used according to the invention is a compoundselected from phenols and mixtures thereof. The phenol component can bea mono- or poly-hydroxylated compound comprising in its molecule atleast one non-fused benzene ring, at least two fused benzene rings or atleast three fused benzene rings, it being possible for one of thesephenolic OH groups to be etherified, replaced with a carboxyl group orreplaced with a group CHO.

The following may be mentioned in particular among the compounds coveredby the definition of Cp: phenol, pyrocatechol, resorcinol, hydroquinone(or benzene-1,4-diol), benzene-1,2,4-triol, pyrogallol (orbenzene-1,2,3-triol), phloroglucinol (or benzene-1,3,5-triol), gallicacid (or 3,4,5-trihydroxybenzoic acid), saligenol (or2-hydroxybenzenemethanol), vanillin (or4-hydroxy-3-methoxybenzaldehyde), vanillyl alcohol (or4-hydroxy-3-methoxybenzenemethanol), vanillic acid (or4-hydroxy-3-methoxybenzoic acid), vanillylmandelic acid (or4-hydroxy-3-methoxymandelic acid), o-cresol, m-cresol, p-cresol,o-cresotic acid (or 2-hydroxy-3-methylbenzoic acid), m-cresotic acid (or2-hydroxy-4-methylbenzoic acid), p-cresotic acid (or2-hydroxy-5-methylbenzoic acid), guaiacol (or 2-methoxyphenol), eugenol(or 4-allylguaiacol), oreosol (or 2-methoxy-4-methylphenol), thymol (or2-isopropyl-5-methylphenol), orcinol (or 5-methylbenzene-1,3-diol),p-anol [or 4-(prop-1-enyl) phenol], salicyclic acid (or2-hydroxy-benzoic acid), chavicol [or 4-(prop-2-enyl)phenol], carvacrol[or 2-methyl-5-(1-methylethyl)phenol or iso-propyl-o-cresol],4-t-butylphenol, butylparaben (or n-butyl 4-hydroxybenzoate),benzoresorcinol (or 2,4-di-hydroxyphenyl phenyl methanone), bisphenol A[or 4,4'-(1-methylethylidene) bisphenol, abbreviated to BpA], bisphenolB [or 4,4'-(1-methylpropylidene)bisphenol, abbreviated to BpB],bis(2-hydroxy-4-methoxyphenyl) methanone, 1-naphthol, 2-naphthol,anthranol (or anthracen-9-ol), anthrarobin (or anthracene-1,2,10-triol),anthralin [or 1,8-dihydroxy-(10H)-anthracen-9-one], anthrarufin (or1,5-dihydroxyanthracene-9,10-dione) and mixtures thereof.

The BHT's and Bsp's of formulae I and II, respectively, may also bementioned among the Cp's which are suitable.

The BHT's are 2,6-di-t-butylphenol compounds of the formula ##STR1## inwhich R is the hydrogen atom or a C₁ -C₁₂ alkyl group with a linear orbranched hydrocarbon chain.

The following in particular are covered by formula I:2,6-di-t-butylparacresol (HG1), 2,6-di-t-butyl-4-butylphenol (HG4),2,6-di-t-butyl-4-t-butylphenol (HGt4), 2,6-di-t-butyl-4-hexylphenol(HG6), 2,6-di-t-butyl-4-(1,1,3,3-tetramethylbutyl) phenol (HGt8) andmixtures thereof.

The Bzp's are 2-benzylphenol compounds of the formula ##STR2## in whichX and Y independently of one another are each the hydrogen atom, a groupOH, a group OMe or a group OEt, it being possible for X and Y, takentogether, to be a 3,4-methylenedioxy radical,

A is H or a radical CH₂ C₆ H₃ XY, in which X and Y are defined asindicated above, and

B is the hydrogen atom or a C₁ -C₁₂ alkyl group with a linear orbranched hydrocarbon chain.

The Cp compounds containing an unsaturated aliphatic side-chain, forexample prop-1-enyl or prop-2-enyl, are used not by themselves but inassociation with at least one other Cp devoid of ethylenic or acetylenicunsaturation on a side-chain. In fact, the Cp compounds which do have anethylenic or acetylenic unsaturation are liable to polymerize under theaction of light. It is therefore of interest, according to theinvention, to associate them with at least one other phenol havinganti-UV properties so as to avoid any polymerization during storage.

The preferred phenol component according to the invention will beselected from BpA, pyrogallol, pyrocatechol, carvacrol, BHT's andmixtures thereof. The most valuable Cp compounds according to theinvention are the BHT's and especially HG1, HGt4, HG4, HG6, HGt5 andHGt6.

The propolis component which forms part of the composition according tothe invention will be a purified Prp, especially a Prp soluble in wateror the customary organic solvents, which is obtained by treating crudePrp with an alcohol, such as MeOH or EtOH, or a water/alcohol mixture.The Prp's obtained by the methods described in DE-A-1 037 651, FR-A-2256 764, FR-A-2 374 030, FR-A-2 594 336, EP-A-0 061 508, EP-A-0 109 993,EP-A-0 135 601 and EP-A-0 310 757, which take the form of white or lightbrown powders or granules, are particularly suitable for this purpose.

The therapeutic composition which is useful in the treatment of theviral diseases caused by the LCV's will comprise the Cp/Prp mixture withan R_(w) of between 100/1 and 650/1, in association with one or moreexcipients appropriate for oral administration, administration byinjection or local administration.

Such a composition will be particularly advantageous when used againstherpes and diseases analogous to herpes. It has in fact been found thatsuch a composition is particularly effective in the treatment of herpessimplex type 1 and type 2, especially the diseases caused by the HSV₁and HSV₁ R strains, which are transmissible by contact between mucosa,on the one hand, and the diseases caused by the HSV₂ strains, which aresexually transmissible and include especially condyloma latum, on theother.

The antiviral composition according to the invention can be prepared bya method known per se. The recommended method consists in mixing the Cpcomponent and Prp component in an appropriate aqueous or oilyphysiological medium at a temperature between RT and 75° C.

BEST MODE

The best mode of carrying out the invention consists in using acomposition of BHT and Prp in which the BHT is 2,6-di-t-butylparacresol(HG1), 2,4,6-tri-t-butylphenol (HGt4), 2,6-di-t-butyl-4-n-hexylphenol(HG6) or 2,6-di-t-butyl-4-(1,1,3,3-tetramethylbutyl) phenol (HGt8), witha ratio of R_(w) of between 135/1 and 680/1.

According to the invention, a novel therapeutic use is recommended,wherein a mixture comprising a phenol component and propolis in a weightratio phenol component/propolis of between 100/1 and 650/1, andpreferably of between 135/1 and 560/1, is used to obtain an antiviraldrug for use in human or veterinary therapeutics against the diseasescaused by lipid capsid viruses, especially the diseases caused by thefollowing strains: (i) HSV₁, HSV₂ and HSV₁ R, and (ii) IV_(A), EBV andZV.

Further advantages and characteristics of the invention will beunderstood more clearly from the following description of ComparativeExperiments and Preparatory Examples. Of course, these data as a wholein no way imply a limitation but are given by way of illustration.

EXAMPLE 1 Comparative Experiments

The following are used: a culture medium containing HG1 atconcentrations of 50 or 25 mg/ml and solutions of Prp at decreasingconcentrations of 0.363 mg/ml, 0.272 mg/ml, 180 mg/ml, 136 mg/ml and0.090 mg/ml. Equal volumes of said culture medium and said solutions areincubated in the presence of HSV₁ R for 1 h at 37° C., with shaking.After centrifugation, the infectious titers are determined in the usualmanner by the so-called limiting dilution method and compared withcontrol samples of HSV₁ R virus, control samples of propolis and controlsamples of HG1, incubated under the same conditions (it was necessary toprepare control samples of excipient since previous experiments haddemonstrated the absence of an effect of the excipient on viruses,especially HSV₁ R).

The method used to measure the interaction between Cp and Prp preciselywas that described by R. F. SCHINAZI et al., Antimicrob. AgentsChemother., 22 (n° 3), pages 499-507 (1982) and reworked by J. C.POTTAGE, ibidem 30 (n° 2), pages 215-219 (1986), incorporating thefollowing definitions:

Y_(a) =infectious titer in the presence of Prp/TV,

Y_(b) =infectious titer in the presence of HG1/TV,

Y_(ab) =infectious titer in the presence of Prp+HG1/TV,

Y_(o) =Y_(a) ×Y_(b).

If:

1°) Y_(ab) <Y_(o), the interaction is synergistic,

2°) Y_(ab) >Y_(o) but < the more active compound by itself, theinteraction is in this case a subadditive reaction,

3°) Y_(ab) >the less active compound by itself, the interaction isantagonistic, and

4°) Y_(ab) >the more active compound but < the less active compound, theinteraction is then called interference.

To simplify the calculations, the infectious titers found in theexperiments on HG1/Prp associations and the control experiments wereexpressed as their decimal logarithm. The results obtained have beencollated in Table I below.

The results in Table I show that:

at the highest concentrations used (Prp 0.363 mg/ml and HG1 50 mg/ml),it is not possible to observe an interaction since propolis by itself isvirucidal at this dose,

at a Prp concentration of 0.272 mg/ml, only an interference effect withHG1 is observed,

on the other hand, at the low Prp concentrations (0.090 to 0.180 mg/ml),there is a synergy with HG1 occurring at a concentration of 25 or 50mg/ml.

In the case in question, there is a synergy when the ratio R_(w)=HG1/Prp is between 135/1 and

                                      TABLE I                                     __________________________________________________________________________    STUDY OF THE ASSOCIATION Prp/HG1 ON THE INFECTIOUS TITER OF HSV.sub.1 R                    Prp + HG1                                                        TV  Prp titer                                                                         HG1 titer                                                                          experiments                                                                         Y.sub.a                                                                           Y.sub.b                                                                          Y.sub.ab                                                                          Y.sub.0                                                                          Interaction                                  __________________________________________________________________________    4.5 3.5 (a)                                                                           2 (f)                                                                              0.5   0.77                                                                              0.44                                                                             0.11                                                                              0.33                                                                             synergy                                      4.5 4.5 (a)                                                                           3 (g)                                                                              2.5   1   0.66                                                                             0.55                                                                              0.66                                                                             synergy                                      5.0 4.0 (a)                                                                           2 (g)                                                                              0     0.8 0.4                                                                              0   0.32                                                                             synergy                                      4.5 2.5 (b)                                                                           2 (f)                                                                              0     0.55                                                                              0.44                                                                             0   0.24                                                                             synergy                                      4.0 1.0 (c)                                                                           1 (f)                                                                              0     0.25                                                                              0.25                                                                             0   0.06                                                                             synergy                                      4.5 1.5 (c)                                                                           2 (f)                                                                              0     0.33                                                                              0.44                                                                             0   0.14                                                                             synergy                                      4.5 3.5 (c)                                                                           3 (g)                                                                              2     0.77                                                                              0.66                                                                             0.44                                                                              0.50                                                                             synergy                                      5.0 3.0 (c)                                                                           2 (g)                                                                              1     0.6 0.4                                                                              0.2 0.24                                                                             synergy                                      4.0   0 (d)                                                                           2 (f)                                                                              0.5   0   0.5                                                                              0.12                                                                              0  interference                                 5.0 1.0 (d)                                                                           2 (g)                                                                              1.0   0.2 0.4                                                                              0.25                                                                              0.08                                                                             interference                                 4.0   0 (e)                                                                           2 (f)                                                                              0     0   0.5                                                                              0   0  (h)                                          __________________________________________________________________________     Notes                                                                         (a) Prp at a concentration of 0.090 mg/ml                                     (h) Prp at a concentration of 0.138 mg/ml                                     (c) Prp at a concentration of 0.180 mg/ml                                     (d) Prp at a concentration of 0.272 mg/ml                                     (e) Prp at a concentration of 0.363 mg/ml                                     (f) HG1 at a concentration of 50 mg/ml                                        (g) HG1 at a concentration of 25 mg/ml                                        (h) excessively high dose of Prp                                         

EXAMPLE 2 Formulation

A mixture of 59 g of white petrolatum, 2.99 g of sorbitan sesquioleateand 3 g of glycerol monooleate is heated to 70-75° C. Heating is stoppedwhen the mixture has become homogeneous, after which 5 g of HG6 and then0.01 g of propolis are added, with stirring. 30 g of water are thenadded at a temperature below or equal to 65° C. and stirring iscontinued until the mixture has cooled to RT. It is homogenized to givean ointment consisting of a water-in-oil emulsion, which can be used asan eye lotion.

EXAMPLE 3 Formulation

56.98 g of white petrolatum, 3.5 g of sorbitan sesquioleate and 3.5 g ofglycerol monooleate are mixed at 70-75° C. When the mixture has becomehomogeneous, heating is stopped and 7 g of HG1 are added. Mixing isresumed and a mixture consisting of 0.02 g of propolis (R_(w) =350/1)and 30 g of water is added at a temperature below about 70° C., withstirring. Stirring is continued until the mixture has cooled to RT,after which it is homogenized to give an ointment consisting of awater-in-oil emulsion, which can be used as an eye lotion.

EXAMPLE 4 Formulation

4.66 g of polyethylene glycol stearate 1500 are mixed with 13 g ofglycerol monostearate, 3 g of glycerol monooleate, 10.5 g of decyloleate, 5.5 g of capric/caprylic triglyceride and 5 g of glycerolisostearate. The mixture is heated gradually to 70-75° C. and heating isstopped as soon as the mixture has become homogeneous. 8 g of HGt4 arethen added and the mixture is stirred slowly. 3 g of propylene glycol,0.3 g of citral, 0.04 g of Prp (R_(w) =400/1) and 47 g of water are thenpoured into the resulting mixture. The mixture obtained is left to coolto RT, with stirring. It is then passed through a homogenizer to give awater-in-oil emulsion having the consistency of a cream.

EXAMPLES 5-12 Formulations

The following compositions, in which only the phenol component ismentioned and the weight ratio R_(w) =Cp/Prp is given in brackets, areobtained by the procedure indicated in Example 4, except that the phenolcomponent HGt4 is replaced with an appropriate amount of another phenol.

Ex. 5: bisphenol A (R_(w) =250/1),

Ex. 6: pyrogallol (R_(w) =270/1),

Ex. 7: carvacrol (R_(w) =300/1),

Ex. 8: pyrocatechol (R_(w) =270/1),

Ex. 9: 2-(3,4-methylenedioxybenzyl)-4-t-butylphenol (R_(w) =340/1),

Ex. 10: 2-(3,4-dihydroxybenzyl)-4-(1,1,3,3-tetramethylbutyl) phenol(R_(w) =450/1),

Ex. 11: HGt8 (R_(w) =420/1),

Ex. 12: HGt5 (R_(w) =190/1).

EXAMPLE 13 Preparation of Purified Propolis

The propolis used in Examples 1-12 above is a purified propolis obtainedby extraction with 80% EtOH (i.e. an EtOH/H₂ O mixture in a weight ratioof about 8/2), as indicated below.

The crude Prp is deposited by the bees on perforated plastic gridsmounted on frames placed in the beehives. These grids, containing thecrude Prp, are removed from the beehives and cooled to -30° C. in afreezer so as to make the crude Prp brittle, after which it is ground ina mortar. The ground material is extracted with 80% EtOH, at a rate of 1part by weight of crude Prp to 10 parts by volume of 80% EtOH, for 24 hat RT, with stirring. The insoluble residue is filtered off. Thefiltrate collected is evaporated under reduced pressure to give a lightbrown dry extract. Yield: 65% by weight, based on the starting crudePrp.

What is claimed is:
 1. An antiviral composition comprising aphysiological acceptable carrier and an antiviral effective amount of asynergistic mixture consisting of(i) from 100 to 650 parts by weight ofa phenol component and (ii) one part by weight of purified propolis. 2.A composition according to claim 1, wherein the phenol component isselected from the group consisting of phenol, pyrocatechol, resorcinol,hydroquinone, benzene-1,2,4-triol, pyrogallol, phloroglucinol, gallicacid, saligenol, vanillin, vanillyl alcohol, vanillic acid,vanillylmandelic acid, o-cresol, m-cresol, p-cresol, o-cresotic acid,m-cresotic acid, p-cresotic acid, guaiacol, eugenol, creosol, thymol,orcinol, p-anol, salicylic acid, chavicol, carvacrol, 4-t-butyl-phenol,butylparaben, benzoresorcinol bisphenol A, bisphenol B,bis(2-hydroxy-4-methoxyphenol) methanone, 1-naphthol, 2-naphthol,anthranol, anthrarobin, anthralin, anthrarufin and mixtures thereof. 3.A composition according to claim 1, wherein the phenol component isselected from the group consisting of(i) the 2,6-di-t-butylphenols ofthe formula ##STR3## in which R is the hydrogen atom or a C₁ -C₁₂ alkylgroup with a linear or branched hydrocarbon chain, and (ii) mixturesthereof.
 4. A composition according to claim 1, wherein the phenolcomponent is selected from the group consisting of(i) the2-benzylphenols of the formula ##STR4## in which X and Y independentlyof one another are each the hydrogen atom, a group OH, a group MeO or agroup EtO, or X and Y, taken together, form a 3,4-methylenedioxyradical,A is H or a radical CH₂ C₆ H₃ XY, in which X and Y are definedas indicated above, and B is the hydrogen atom or a C₁ -C₁₂ alkyl groupwith a linear or branched hydrocarbon chain, and (ii) mixtures thereof.5. A composition according to claim 1, wherein the phenol component isselected from the group consisting of the following compounds:(a)2,6-di-t-butylparacresol, (b) 2,4,6-tri-t-butylphenol, (c)2,6-di-t-butyl-4-(2,2-dimethylpropyl)phenol, (d)2,6-di-t-butyl-4-n-hexylphenol, (e)2,6-di-t-butyl-4-(1,1,3,3-tetramethylbutyl) phenol (f) bisphenol A, (g)pyrogallol, (h) pyrocatechol, (i) carvacrol, and (j) mixtures thereof.6. A composition according to claim 1, wherein the weight ratio phenolcompound/propolis is between 135/1 and 560/1.
 7. A method of treatinglipid capsid viruses in an animal in need of such treatment whichcomprises administering to said animal an antiviral effective amount ofa synergistic mixture consisting of (i) from 100 to 650 parts by weightof a phenol component, and (ii) one part by weight purified propolis. 8.The method of claim 1 in which the weight ratio of phenol component topropolis is between 135/1 and 560/1.
 9. The method of claim 8 in whichthe viral disease is herpes simplex.
 10. The method of claim 7 in whichthe viral disease is herpes simplex.
 11. Method according to claim 1,wherein the weight ratio phenol component/propolis is between 135/1 and560/1.